**3. Therapy with biologics**

During the past decade, a new class of therapeutics called biologics has been introduced, and their use led to successful treatment outcomes for lupus and several other inflammatory diseases. Biologics are proteins capable of binding to specific receptors present in immune cells and modulating the functions of immune cells. Overall, biologics are now being developed against several types of immune cells to modulate the functions of the immune system to treat the disease (**Figure 1**). Belimumab, a biologic that targets B cells, has been approved for the treatment of SLE. A number of biologics are now being studied in clinical trials (**Table 1**).

### **3.1 Anifrolumab**

Anifrolumab, a type I interferon receptor antagonist, was recently approved in 2021 for the treatment of SLE in patients with moderate to severe symptoms [107].

#### **Figure 1.**

*Mechanism of action of belimumab and rituximab. Belimumab competitively inhibits BAFF binding to the BAFF receptor required for B-cell survival and maturation. Similarly, rituximab inhibits CD-20 on the surface of B cells, which inhibits B-cell maturation into plasma cells.*


*Recent Advances in SLE Treatment Including Biologic Therapies DOI: http://dx.doi.org/10.5772/intechopen.105558*


**Table 1.** *Biologics currently under clinical trial for the treatment of SLE.*

*Recent Advances in SLE Treatment Including Biologic Therapies DOI: http://dx.doi.org/10.5772/intechopen.105558*

Previous studies have indicated that type I IFN plays a key role in the pathophysiology of SLE and increased type I IFN signaling causes increased disease activity. Previous studies have demonstrated that type I interferon plays a key role in the pathophysiology of SLE and increased type I interferon signaling results in increased disease activity [108, 109]. The efficacy and safety data were obtained from the two TULIP phase III trials, and the MUSE phase II trial led to the approval of Anifrolumab [108, 110–113]. These trials were randomized, double-blinded, and placebo-controlled trials involving patients with moderate to severe SLE, who were under standard therapy with glucocorticoids, antimalarials, or immunosuppressants. In these trials, SLE patients treated with Anifrolumab experienced an overall reduction in disease activity in almost all organs, especially in skin and joints, and achieved a considerable reduction in the requirement of corticosteroids [107]. Further data suggest that Anifrolumab prevents organ damage occurring due to SLE or by chronic medications, including steroids, and thus, it improves the quality of life of SLE patients. The major adverse effects of Anifrolumab usage are mostly respiratory tract associated, including nasopharyngitis, bronchitis, and upper respiratory tract infections [107, 108, 110–112].

#### **3.2 Rituximab**

Rituximab (RTX) is a monoclonal antibody targeting CD20, a membrane receptor present on the surface of B-lineage cells, as a transmembrane protein excluding plasma cells and pro-B cells [114–116]. The interaction between CD20 and RTX results in the inaccessibility of CD20 for its ligand, leading to the inhibition of distinct cell survival pathways and B-cell maturation signals. Furthermore, the binding of rituximab with this membrane receptor results in the induction of both antibody and cell-mediated cytotoxicity, which causes the reduction of CD20<sup>+</sup> cells [116]. The FDA initially approved RTX for non-Hodgkin's lymphoma; it has also provided promising results in rheumatoid arthritis (RA) treatment. Based on recent studies, RTX may have a beneficial role in inflammatory diseases [117]. In 2002, RTX was used to treat SLE; RTX was used in combination with steroids and cyclophosphamide; five out of six patients developed significant improvement in response to this treatment [118, 119]. RTX showed significant beneficial results in phase I and phase II clinical trials; another retrospective clinical trial performed on 45 patients showed the beneficial effects of RTX [120]. Phase II and phase III trials, known as the EXPLORER trial, were conducted based on the positive outcomes of RTX treatment in SLE. The main aim of this trial was an extensive analysis of RTX efficacy in nonrenal SLE. This trial comprised 257 patients who were kept on a stable dose of one immune-suppressive drug were included in this study; these participants were treated by following a standard care of treatment, along with either two intravenous RTX 1 g doses (one at 14 days following the start of the trial and the other at 6 months) or placebo. The use of methotrexate, azathioprine, mycophenolate mofetil (MMF), and corticosteroids was allowed for continuation under the supervision of treating medical specialists. The primary endpoint of this study was to achieve and maintain a robust clinical response or a partial clinical response by the 52nd week. The secondary endpoint was to assess the clinical response of patients at 52 weeks, along with the improvement in quality of life. The steroid-sparing benefit of RTX was also evaluated as a secondary endpoint. No difference between the primary and secondary endpoints was observed in the RTX and placebo groups for this EXPLORER trial. Another trial, known as LUNAR, was conducted in SLE patients to investigate the efficacy of RTX

in lupus nephritis [121]. It was a double-blind RCT with 144 participants, and the amount of RTX dosage and other standards of care treatments were similar to the EXPLORER trial. There was no significant difference between the RTX and placebo cohorts' primary and secondary endpoints [121]. Although the endpoints of phase II and phase III RCTs for rituximab failed, this does not necessarily mean that the drug failed; trial design can be considered as a possible potential reason for this failure. RTX has some adverse effects. RTX use is contraindicated in advanced heart failure (New York Heart Association Class IV) [122]. Since RTX is an immunosuppressant, infection is a significant concern with rituximab treatment. Several studies have shown that repeated use of RTX can be associated with decreased immunoglobulin levels. Patients who already have low immunoglobulins or are already taking other immunosuppressant medication have a higher rate of infection while taking RTX treatment [123].

#### **3.3 Belimumab**

Belimumab (BEL) is a monoclonal antibody that targets BAFF [124] and is referred to as a B lymphocyte stimulator (BLyS); these factors are secreted by myeloid-lineage cells. The binding of BAFF with BAFF-R (receptor present on B naïve cells) leads to the activation of specific signaling, promoting survival and differentiation of the naïve B cells [125]. BEL binds with these soluble stimulatory factors, resulting in the inhibition of BLyS binding with BAFFR [124, 126]. BEL was first approved for adult SLE in 2011, with remarkable success in adult SLE treatment. A study performed on mice models has demonstrated the importance of BAFF in SLE progression, where deletion of the Baff gene prevented SLE progression in diseased mice [127]. Neutralizing BAFF with specific immunogenic approaches in mice has shown a significant reduction in disease progression [128, 129]. Patients suffering from SLE have shown a higher level of BAFF than healthy controls, and the level of BAFF was found to be increased in the correlation with SLE progression [130–132]. Efficacy of BEL against SLE was initially studied in a large double-blind phase III RCTs [133, 134]. In this study, 10 mg/kg intravenous BEL was given in addition to the background standard of care therapy with a 2-week interval between the first three doses and then every 4 weeks. SLE patients who had active CNS involvement or lupus nephritis were excluded. Participants were kept on stable doses of corticosteroids, antimalarials, nonsteroidal anti-inflammatory drugs, and immunosuppressive drugs for 30 days before this trial. The primary endpoint was the SLE responder index-4 at week 52. This accounted for ≥4-point depletion in the SLE disease activity index (SELENA-SLEDAI) score. The significant difference between the patient and placebo arm of the trial study has given promising results for BEL use against SLE. Consistently, BEL effectively improved SLE in all the trials compared to placebo. BEL has also shown steroid-sparing effects in these patients [135, 136]. Moreover, in the ongoing international observational clinical studies, BEL is being used as a part of the treatment routine in more than 700 patients and has shown remarkable beneficial effects [137–139]. Despite being a remarkable drug against SLE, and being an immunosuppressor drug, BEL also has some contraindications along with minor side effects. Major infections have been observed in the patients treated with belimumab. Appropriate precautions and medical advice should be taken by the patient suffering from chronic infection before the BEL treatment [124]. In patients with refractory LN, studies showed that adding belimumab to a therapy regimen that included rituximab/CYC was safe and effective [140]. Moreover, BEL, despite being a safe drug,

not all the patients treated with BEL show significant improvement in their disease. This suggests the involvement of other vital pathways playing a role in SLE development which challenges the generalized use of BEL against SLE.
